Investigation of pathogenesis and progression of interstitial disorder mediated by FcRn in glomerulonephritis.

在肾脏中，通过肾小球过滤的蛋白质通过近端小管的内吞作用被重吸收，以避免肾脏大量蛋白质（如白蛋白、β_2-微球蛋白和几种激素）的损失。尽管白蛋白的重吸收可以防止这种主要血浆蛋白通过尿液大量流失，但白蛋白的过度重吸收可能是慢性肾脏疾病发生和进展的一个因素。因此，肾脏似乎对蛋白质的再吸收和分解代谢有一定的限制，在肾脏疾病中发现的过滤负荷大大增加。另一方面，在尿液中也发现了免疫球蛋白，如IgG、IgA及其片段。与其他蛋白质类似，这些分子的吸收似乎受到近端小管内吞途径的调节，但其机制尚不完全清楚。最近的一项研究发现，参与IgG A转运的新生儿Fc受体（FcRn）在肾近端小管上皮细胞中表达，FcRn在多个上皮和内皮细胞中表达。提示FcRn可能在管状液中IgG的重吸收中起重要作用。然而，到目前为止，没有直接证据表明受体介导的IgG在人肾近端小管上皮细胞内吞作用。为了探索FcRn在近端小管中的生理作用，我们使用人肾近端小管上皮细胞（rptec）检测了IgG的转运。FcRn在rptec中表达，并与β_2-微球蛋白物理关联，保留特异性ph依赖性IgG结合能力。人IgG以ph依赖性方式结合在rptec细胞表面。人IgG转运试验显示，受体介导的完整IgG在rptec中的经上皮转运是双向的，并且需要形成酸化的细胞内区室。双免疫荧光法显示，内化的人IgG在rptec细胞质中被标记，并与FcRn共定位。这些数据定义了fcrn相关IgG在RPTEC单层中的转运机制。少

In the kidney, proteins filtered through glomeruli are reabsorbed by endocytosis along the proximal tubules to avoid renal loss of large amounts of proteins such as albumin, β_2-microglobulin and several hormones. Although the reabsorption of albumin prevents the loss of large amounts of this major plasma protein via the urine, excess reabsorption of albumin may be a factor for the development and progression of chronic renal diseases. Thus, the kidney appears to have a limit on the amount of protein which can be reabsorbed and catabolized at the greatly increased filtered-loads found in renal diseases. On the other hand, immunoglobulins such as IgG, IgA, and their fragments have also been found in the urine. Similar to other proteins, absorption of these molecules seems to be regulated by the endocytosis pathway in the proximal tubules, but the mechanisms are not fully understood. A recent study revealed that the neonatal Fc receptor (FcRn), which is involved in the transport of IgG a … More cross several epithelial and endothelial cells, was expressed in renal proximal tubular epithelial cells. It was suggested that FcRn may play an important role in the reabsorption of IgG from the tubular fluid. However, to date there is no direct evidence for receptor-mediated endocytosis of IgG in the renal proximal tubular epithelial cells in humans. To explore the physiological roles of FcRn in the proximal tubules, we examined IgG transport using human renal proximal tubular epithelial cells (RPTECs). FcRn was expressed in RPTECs and physically associated with β_2-microglobulin, preserving the capacity of specific pH-dependent IgG binding Human IgG was bound to the cell surface of RPTECs in a pH-dependent manner. The human IgG transport assay revealed that receptor-mediated transepithelial transport of intact IgG in RPTECs was bidirectional and that it requires the formation of acidified intracellular compartments. Using double immunofluorescence, internalized human IgG was shown to be marked in cytoplasm of RPTECs and colocalized with FcRn. There data define the mechanisms of FcRn-associated IgG transport in the RPTEC monolayers. Less